Structural Insight into the Dehydration and Hydration Behavior of Naltrexone and Naloxone Hydrochloride. Dehydration-Induced Expansion versus Contraction

For the chemically and structurally related antagonists naltrexone and naloxone, hydrate and anhydrate forms exist for the hydrochloride salts, the generic forms that are oil the market. The hydration/dehydration behavior of these salts was studied by applying hot-humidity stage X-ray powder diffraction, microscopy, differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR. The combination of these techniques shows consistent results and yields a detailed conversion scheme. A new Crystal Structure, determined from X-ray powder diffraction data, for naltrexone hydrochloride anhydrate is presented. The Structure was solved by the DASH program and was refined with TOPAS. This new structure, together with the already known structures of naltrexone and naloxone hydrochloride, enabled us to investigate the influence of the subtle molecular differences between the two antagonists and the role of water on Structural properties in the solid state. All known hydrate and anhydrate forms of naltrexone and naloxone hydrochloride crystallize in the orthorhombic space group P2(1)2(1)2(1), although the crystal packings show clear differences. Dehydration causes in both cases no breaking of the symmetry. but the change in unit Cell for naltrexone is profoundly different front that of naloxone. Dehydration of naltrexone hydrochloride tetrahydrate takes place with shrinkage of the volume of the Unit cell, whereas dehydration of naloxone hydrochloride dihydrate results in all expansion of the unit cell. The H-bonding patterns corresponding to the two opioids seem to be footprints for the crystal structures and for the hydration/dehydration behavior of the two antagonists. Despite naltrexone and naloxone hydrochloride are chemically and Structurally related and show Similarities in their biological behavior, the overall hydration and dehydration process is fundamentally different.